Among the histopatholigical alterations that are found at autopsy in brains of nondemented elderly humans are dystrophic axons, granular degneration of myelin and, in some cases, senile plaques (SP). Although SP are also found in Alzheimer's disease (AD), they are morphologically different fromthose in the non-demented brain. We hypothesize that SP evolve from nonfibrillar preamyloid deposits that undergo fibrillogenesis promoted by physical and biochemical changes in Abeta. The long-live amyloid deposits are progressively glycated, which elicits recruitment and activation of microglia and astrocytes and production of neurotoxins and other amyloid associated molecules (e.g., apo-E). The ensuing reaction leads to further amyloid deposition and local neuritic dystrophy. In the aged brain dystrophic neurites in SP have coarse granular ubiquitin-immunoreactivity. In contrast, paired helical filament (PHF) immunoreactivity is detected in AD. Ubiquitin is also found in dystrophic axons that are consistently found in the limbic gray matter of the elderly brain. It is our hypothesis that progressive neuroaxonal dystrophy may be responsible for age- associated cognitive impairment not due to early AD. Ubiquitin also labels granular degeneration of myelin, which is an inevitable consequence of aging, that may underlie motor and mental slowing of the elderly. To further elucidate the role of neuritic and axonal dystrophy and SP in cognitive impairment of the elderly, we will pursue three major specific aims: 1) Determine if there are qualitative differences in SP brains of people with cognitive impairment compared to those without impairment by analyzing the type of SP neurites (dystrophic vs. PHF types), apolipoprotein-E (apo-E) and advanced glycation endproducts (AGE) immunoreactivity and presence of astrocytes and microglia. These qualitative analyses will be correlated with quantitative immunoassays for apo-E and AGE, the latter with respect to brain fractions enriched in Abeta of PHF. 2) To characterize and objectively measure the amount of neuritic dystrophy and granular myelin degeneration by image analysis of immunostained sections and immunoassays (ELISA & dot blots) for ubiquitin in fresh tissue. 3) Characterize neuroaxonal dystrophy in limbic gray matter with double immunolabeling, laser confocal microscopy and immunoelectron microscopy and immunoelectron microscopy with respect to cellular and non-cellular components of the neuropil.